Why do biomolecules retain activity when attached to some surfaces (e.g., the cell membrane) and yet almost invariably unfold and inactivate when attached to others (e.g., many artificial surfaces)? And how can we recreate the former effect to produce artificial surfaces on which attached biomolecules similarly retain their function? To date our ability to address these important questions has been hampered by an acute lack of quantitative experimental methods for measuring the thermodynamics of biomolecule-surface interactions. That is, despite a large body of qualitative literature describing how adsorption alters biomolecular structure, and a large number of empirical studies searching for adsorption- resistant surfaces, quantitative, experimentally testable insights into how and why this occurs have proven elusive. Thus motivated, we propose here the development and validation of a novel experimental (electrochemical) approach to measuring the folding free energy of biomolecules site-specifically attached to well-defined macroscopic surfaces. Comparison with the folding free energy in bulk solution then informs on the thermodynamics -and thus mechanisms- underlying biopolymer-surface interactions. To date we have employed this approach to characterize the easily modeled folding of a surface-confined DNA stem-loop in studies that have, for the first time, defined experimentally the extent to which, and mechanisms by which a specific biomolecule interacts with a range of well-defined, macroscopic surfaces. Here we propose a two-year research program aimed at adapting this quantitative experimental tool to the study of protein-surface interactions.